A major neurological complication in very low birth weight infants is the development of periventricular leukomalacia and ventriculomegaly, with subsequent cerebral palsy and cognitive impairment. The primary pathological hallmark of this condition is the loss of myelin and oligodendrocytes. Here we seek to explore the cellular and molecular consequences of oligodendrocyte loss during this stage of neurodevelopment. In particular, we hypothesize that oligodendrocyte loss will lead to secondary changes in axonal morphology and hence behavior. A rodent model for periventricular leukomalacia involving chronic sublethal hypoxia will be characterized in detail for alterations in oligodendrocyte/axon interaction and axonal morphology. These changes will be correlated with behavioral deficits. Preliminary data implicate suppression of the oligodendrocyte proteins Nogo and MAG during hypoxia in the development of ectopic axonal sprouting. To verify the role of these particular proteins, mice lacking Nogo, MAG or the NogoReceptor will be compared with those exposed to chronic sublethal hypoxia. Similarities between the mutant mice and the hypoxic mice will support the hypothesis that these proteins contribute to the pathophysiology of periventricular leukomalacia. In addition, the synergistic effects of hypoxia plus Nogo, MAG or Nogo receptor gene deletion will be analyzed. This may provide further support for the hypothesis that hypoxia-induced deficits in oligodendrocytes lead to maladaptive changes in axonal morphology. Together these studies should advance our current understanding of the interactions between oligodendrocytes and axons under conditions similar to those experienced by very low weight birth weight infants. Such knowledge may lead to the development of novel therapeutic approaches aimed at lessening the long-term neurological sequela of prematurity.